Mono- or disubstituted 1,2,4,oxadiazoles which are substituted by at least 1-N-substituted carbamoyl group

ABSTRACT

1,2,4-Oxadiazoles having as 3- and 5-substituents a hydrogen atom, an aliphatic, cycloaliphatic, araliphatic, aryl or heterocyclic group, or a carbamoyl group of the formula -- CONR 1  R 2  where R 1  &amp; R 2  which can be the same or different, are hydrogen atoms or aliphatic, cycloaliphatic, araliphatic or aryl groups or, taken with the N atom, a heterocvolic ring; provided that at least one of the 3- or 5-substituents is an N-substituted carbamoyl group. Antimicrobial activity, and particularly antiviral, antiparasitic and antibacterial activity is shown in this group. The corresponding oxadiazolins are also described and are useful intermediates in the preparation of the oxadiazoles.

This application is a continuation-in-part of application Ser. No.253,807 of Gregory et al., filed May 16, 1972 now abandoned.

This invention relates to new oxadiazole derivatives, processes for thepreparation thereof and pharmaceutical compositions containing the same.

We have found that interesting physiological activity, particularlyantimicrobial activity, including antiviral, antiparasitic andantibacterial activity, is shown by a group of 3 and/or 5-substituted1,2,4-oxadiazole compounds.

In one aspect the invention provides novel 1,2,4-oxadiazole compounds ofthe general formula ##SPC1##

Where R⁶ represents R, where R represents a hydrogen atom or analiphatic, cycloaliphatic, araliphatic, aryl or heterocyclic group; or acarbamoyl group of the formula --CONR¹ R² where R¹ and R², which may bethe same or different, represent hydrogen atoms, aliphatic,cycloaliphatic, araliphatic or aryl groups or, together with theintervening N, represent a heterocyclic ring; and R⁷ represents R, whereR is as defined above or a carbamoyl group of the formula --CONR³ R⁴,where R³ and R⁴ are as defined for R¹ and R² ; provided that at leastone of R⁶ and R⁷ is an N-substituted carbamoyl group.

Thus, for example, R may represent an aryl group which is preferablymono- or bi-cyclic, such as a phenyl, naphthyl or biphenylyl group; oran araliphatic group such as an aralkyl, aralkenyl or aralkynyl groupe.g. a benzyl, phenethyl, phenylethynyl or styryl group. R mayalternatively represent a heterocyclic group, e.g. a 5- or 6-memberedgroup such as a furyl, thienyl or pyridyl group. Such aryl, araliphaticand heterocyclic groups may carry one or more ring substituents such aslower alkyl, lower alkoxy, lower alkylthio, lowr alkylsulphinyl, loweralkylsulphonyl, amino, acylamino, cyano, thiocyanato or nitro groups orhalogen atoms, for example, a tolyl, p-methoxyphenyl, p-nitrophenyl,p-chlorophenyl, p-methylthiostyryl, p-methylsulphinylstyryl orp-methoxystyryl group. The acyl portions of the acylamino may forexample be straight or branched lower alkanoyl groups. When an aminoring substituent is present the compounds may form salts e.g. withstrong acids such as hydrochloric and sulphuric acid. Where R representsan aliphatic group this may for example be an alkyl, alkenyl or alkynylgroup such as a methyl or ethyl group, an allyl group, an ethynyl groupor a propargyl group, which may carry heterocyclic groups assubstituents e.g. 5- or 6-membered groups such as furyl, thienyl orpyridyl groups which may themselves carry substituents.

When R is an aliphatic group it is preferably saturated. Where R is aheterocyclic group or carries a heterocyclic substituent, the heteroatom(s) is preferably S and/or N, and the group is preferably not anitrofuryl group.

Where R is a cycloaliphatic group this may for example be a cycloalkylgroup having 3-10 carbon atoms, e.g. a cyclohexyl group.

R¹, R², R³ and R⁴ may, for example, represent aliphatic groups which maybe substituted by functional groups such as hydroxy groups, especiallylower alkyl groups such as methyl, ethyl, propyl, n-butyl, t-butyl or 2-hydroxyethyl groups, alkenyl groups such as allyl groups or alkynylgroups such as a propargyl group; aryl groups especially monocyclic arylgroups such as phenyl groups, which may carry one or more alkyl oralkoxy substituents; aralkyl, aralkenyl or aralkynyl groups especiallymonocyclic groups such as benzyl groups or cycloaliphatic groupsespecially monocyclic cycloalkyl groups such as cyclohexyl groups orcaged cycloalkyl groups such as adamantyl groups. R¹ and R² or R³ and R⁴may together with the intervening N represent a substituted orunsubstituted nitrogen-containing heterocyclic group, which may containa further hetero atom such as oxygen or nitrogen, e.g. a piperidino,morpholino, pyrrolidin-1-yl, piperazin-1-yl, 4-lower-alkylpiperazin-1-ylor 3-azabicyclo-(3,2,2)-nonan-3-yl group. These heterocyclic groups maybe substituted e.g. by the substituents described above for heterocyclicR groups.

In general each of the substituents R, R¹, R², R³ and R⁴ preferably hasless than 20 carbon atoms; aliphatic groups preferably have up to 6carbon atoms and alkyl, alkenyl and alkynyl portions of aralkyl,aralkenyl or aralkynyl groups preferably have up to 6 carbon atoms.Heterocyclic groups preferably have 5-10 ring members. Cycloalkyl groupspreferably have 3-10, especially 3-7, carbon atoms.

It will be understood from the above that preferred compounds inaccordance with the invention are generally compounds of the formula Iwherein: R⁶ represents R, where R is hydrogen; an alkyl, alkenyl, oralkynyl group containing up to 6 carbon atoms or such a groupsubstituted with a furyl, thienyl, or pyridyl group; a cycloalkyl grouphaving 3-10 carbon atoms; a phenyl, naphthyl, biphenylyl, benzyl,phenethyl, phenylethynyl, styryl, furyl, thienyl or pyridyl group orsuch a group substituted with one or more lower alkyl, lower alkoxy,lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, amino,lower alkanoyl amino, cyano, thiocyanato or nitro groups or a halogenatom; or a carbamoyl group of the formula --CONR¹ R², where R¹ and R²which may be the same or different each represents hydrogen, an alkyl,alkenyl, or alkynyl group containing up to 6 carbon atoms or such agroup substituted by hydroxy; phenyl or phenyl substituted with one ormore alkyl or alkoxy substituents; benzyl; cycloalkyl containing 3-10carbon atoms; a caged cycloalkyl group; or, together with theintervening nitrogen atom, represent a piperidino, morpholino,pyrrolidin-1-yl, piperazin-1-yl, 4-lower-alkylpiperazin-1-yl, or3-azabicyclo-(3,3,2)-nonan-3-yl group or such a group substituted by oneor more lower alkyl, lower alkoxy, lower alkylthio, loweralkylsulphinyl, lower alkylsulphonyl, amino, lower alkanoylamino, cyano,thiocyanato, or nitro groups or a halogen atom; and R⁷ represents R,where R is as defined above, or a carbamoyl groups of the formula--CONR³ R⁴, where R³ and R⁴ are as defined above for R¹ and R² ;provided that at least one of R⁶ and R⁷ is an N-substituted carbamoylgroup.

Particularly preferred, by virtue of their physiological activity, arethose compounds of the general formula I in which R represents an arylgroup, especially a bicyclic and/or substituted aryl group, or anaraliphatic group, which may also be substituted. The preferred R groupsthus possess at least 7 carbon atoms. Preferred examples of substituentswhich may be present on aryl or araliphatic groups are alkyl (e.g. C₁₋₆alkyl), alkoxy (e.g. C₁₋₆ alkoxy), alkylsulphinyl or alkylthio (e.g.C₁₋₆ alkyl), thiocyanato or nitro groups, and halogen atoms. Examples ofsuch R groups are a tolyl, α-naphthyl, biphenylyl, p-methoxyphenyl,p-chlorophenyl, p-methylsulphinylstyryl or p-methylthiostyryl group, ora hydrogen atom. Carbamoyl groups of particular interest, especiallywhen an R group as just mentioned is also present, are those in whichR¹, R², R³ or R⁴ represents an adamantyl group, or wherein R¹ and R² orR³ and R⁴ are both methyl, ethyl or n-propyl groups or, together withthe intervening nitrogen atom, a nitrogen-containing heterocyclic groupe.g. a piperidino group such as described above.

The compounds of formula I may be prepared by any convenient method, inparticular by reaction of a compound of the general formula ##SPC2##

(where R⁸ and R⁹, which may be the same or different, represent R asdefined above, a group of the formula --CONR¹ R² or --CONR³ R⁴ asdefined above or a carboxylic acid group or a reactive derivativethereof, provided that at least one of R⁸ and R⁹ represents a carboxylicacid group or a reactive derivative thereof) with a nitrogen base of theformula R¹ R² NH or R³ R⁴ NH (where R¹, R², R³ and R⁴ are as definedabove) or, where a carboxylic acid of formula II is used, with anisocyanate of the formula R¹ NCO or R³ NCO.

The reactive derivative may be, for example, an ester or an acid halide,e.g. chloride, symmetrical or mixed anhydride or azide. The reactivederivatives are most conveniently the alkyl esters having 1-6 carbonatoms in the alkoxy moiety, e.g. the methyl or ethyl ester; araliphaticesters e.g. the benzyl ester; or aryl esters, e.g. p-nitrophenyl orp-chlorophenyl esters.

Where the compound of formula II is base-sensitive, e.g. when R⁸ or R⁹is hydrogen, it is preferred to use an acid azide or halide, e.g.chloride, as reactive derivative. Such acid chlorides or azides mayconveniently be prepared from the corresponding esters via thehydrazides. Where the reactive derivative is an ester, this isconveniently reacted with an excess of the nitrogen base either alone orin an inert solvent such as an alcohol, e.g. ethanol or methanol, acyclic ether such as dioxan, a hydrocarbon solvent, such as toluene or ahalogenated hydrocarbon solvent such as chloroform. The reaction ispreferably effected at the reflux temperature of the system.

Reaction of the acid azide or halide is desirably effected in an inertsolvent, e.g. a halogenated hydrocarbon solvent such as chloroform or anester such as ethyl acetate, at ambient temperature. Where using an acidhalide, an acid-binding agent is preferably present, e.g. pyridine,propylene oxide or triethylamine.

The amide formation can also be effected by reacting a carboxylic acidof formula II with the nitrogen base in the presence of awater-abstracting agent e.g. a diimide such asdicyclohexylcarbonyldiimide or carbonyldiimidazole; or alternativelywith an isocyanate R¹ NCO or R³ NCO giving a product in which R⁶ and/orR⁷ represents --CONHR¹ or --CONHR³ respectively.

The 1,2,4-oxadiazole ring system itself can be synthesised using anyconvenient method.

In particular, the compounds of formula II and certain products offormula I can be prepared from correspondingly substituted amidoximesemploying O-acylation and subsequent cyclisation, for example, usingacid halides, anhydrides, azides, amides, esters or orthoesters. Theacylation may be carried out where necessary in the presence of an acidbinding agent such as pyridine, propylene oxide or triethylamine.

In one embodiment of this method, an amidoxime of the formula ##STR1##(where R¹⁰ represents R as defined above) is reacted with an oxalic acidderivative of the formula HalCOX where Hal represents a halogen atom,especially chlorine, and X a group --CONR³ R⁴ or an esterifiedcarboxylic acid group, as described in relation to R⁸ and R⁹, forexample a lower (C₁₋₆) alkoxycarbonyl group, e.g. an ethoxycarbonylgroup, to yield either (a) a product of the formula I in which R⁶represents R and R⁷ represents a group of the formula CONR³ R⁴ or (b) anintermediate of the formula II in which R⁸ represents R and R⁹represents an esterified carboxylic acid group.

In another embodiment of the method an amidoxime of the formula III,where R¹⁰ represents an esterified carboxylic acid group, is reactedwith the derivative of formula HalCOX as defined above to yield an esterof the formula II in which R⁸ represents an esterified carboxylic acidgroup and R⁹ represents an esterified carboxylic acid group or a groupof the formula --CONR³ R⁴. The reaction is advantageously carried out inthe presence of an acid binding agent, such as pyridine, propylene oxideor triethylamine.

In a further embodiment an amidoxime of the formula III in which R¹⁰represents an esterified carboxylic acid group is reacted with an acidhalide of the carboxylic acid RCO₂ H where R is as defined aboveyielding an ester of the formula II where R⁸ represents an esterifiedcarboxylic acid group and R⁹ represents R as defined above. The reactionis advantageously carried out in the presence of an acid binding agent,such as pyridine, propylene oxide or triethylamine.

Alternatively the amidoxime of formula III where R¹⁰ represents R, anesterified carboxylic acid group or a group --CONR¹ R² is reacted with aglyoxylic acid derivative of the formula HCO X where X is as definedabove to yield an oxadiazoline of formula ##SPC3##

which may be oxidised to give the corresponding oxadiazole of formulaII, or where X and/or R¹⁰ represents an esterified carboxylic acidgroup, may be reacted with an amine HNR³ R⁴ to give an oxadiazoline offormula ##SPC4##

where R⁸ represents R as defined above or a group --CONR¹ R² and R⁹represents a group --CONR³ R⁴ as defined above. Where R¹⁰ and X bothrepresent an esterified carboxylic acid group, R⁸ in the product formedof formula V represents a group CONR¹ R² where R¹ and R² are identicalto R³ and R⁴ in R⁹. These oxadiazolines (and those wherein R⁹ representsR) can be oxidised to yield a product of formula I and are themselves ofinterest as intermediates and accordingly form a further feature of thepresent invention.

Compounds of the formula II (in which R⁹ represents a hydrogen atom andR⁸ represents an esterified carboxylic acid group) or compounds offormula I (in which R⁷ represents a hydrogen atom and R⁶ represents agroup --CONR¹ 2²) may be prepared by reacting an amidoxime of formulaIII, where R¹⁰ represents an esterified carboxyl group or a group--CONR¹ R², with an orthoformate, e.g. triethyl or trimethylorthoformate in the presence of a Lewis acid such as boron trifluorideor its etherate; or with formyl fluoride, conveniently at reducedtemperature e.g. -78° to room temperature, in an inert solvent.Alternatively, this reaction may be carried out with a Meerwein reagent(e.g. a dialkyl acetal of dimethylformamide) or the Wilsmeier-Haackreagent (phosphorus oxychloride and dimethylformamide).

In general, the preparation of a compound of formula I or formula II,whether substituted or unsubstituted at the 5-position, from anamidoxime of formula III may be effected in an inert solvent.Alternatively an excess of the reagent may be used, for example whenusing an orthoformate as reagent. Where acid halides are used,halogenated hydrocarbon solvents such as chloroform are particularlysuitable and an acid-binding agent is preferably present, e.g. pyridine,propylene oxide or triethylamine.

The reaction with the amidoxime is conveniently effected at an ambienttemperature or a moderately elevated temperature, for example the refluxtemperature of the system.

The oxidation of an oxadiazoline to an oxadiazole is convenientlyeffected, for example, using manganese dioxide, potassium or sodiumpermanganate, sodium nitrite, ferric chloride, palladised charcoal andair, chloranil or related quinones. This reaction is convenientlyeffected in a solvent the nature of which will depend upon the oxidisingagent used. Suitable solvents include for example methanol, chloroformand ethyl acetate.

The temperature at which the oxidation is carried out will also dependon the oxidising agent used but will generally be between 0° to 100° C.

It will be appreciated that for compounds of the formula I in which Rrepresents an aryl or araliphatic group carrying a substituent, it maybe preferable first to prepare a compound of formula I having adifferent substituent by a method as set forth above, which substituentis thereafter converted into the desired substituent. Thus for example,if it is desired that R be an aminophenyl or a cyanophenyl group, it isconvenient first to prepare a compound in which R is nitrophenyl, thenitro group being then reduced to an amino group, which latter may then,if desired, be converted to, for example, a cyano group or halogen atome.g. by a Sandmeyer reaction. Furthermore compounds bearingalkylsulphinyl and alkylsulphonyl groups in the group R mayadvantageously be prepared from the corresponding alkylthio compounds byoxidation, for example using peracetic acid or aqueous hydrogenperoxide; where it is desired to form an alkylsulphinyl group, ingeneral approximately one equivalent of oxidising agent will be used.

It should further be noted that the oxidation of such substituents inthe group R in a corresponding oxadiazoline ring can yield theoxadiazole product of formula I and this constitutes a variation of theoxidation method described above.

As stated above, interesting antiviral activity has been shown in thegroup of compounds in accordance with the invention, principally againstRhinovirus strains, particularly Rhinovirus Serotype 1 (previously knownas M1), and Rhinovirus Serotype 9 (previously known as H9).3-Adamantylcarbamoyl 1,2,4-oxadiazole has shown noteworthy activityagainst Influenza A2 and Herpes simplex viruses. The following Table Ilists a number of compounds identified with respect to formula I havingespecially high activity against Rhinovirus, especially the Serotypes 1and 9.

                  Table I                                                         ______________________________________                                                                     Rhinovirus                                         R.sup.6     R.sup.7        Serotype                                         ______________________________________                                        C.sub.10 H.sub.7 (α)                                                                Et.sub.2 NCO     1                                                p-MeO-phenyl                                                                              Et.sub.2 NCO     1                                                CONMe.sub.2 p-Cl-phenyl      1                                                CONMe.sub.2 C.sub.10 H.sub.7 (α)                                                                     1                                                trans-p-MeS-                                                                              Me.sub.2 NCO     1, 9                                             styryl                                                                        p-MeO-phenyl                                                                              piperidinocarbonyl                                                                             1, 9                                             C.sub.10 H.sub.7 (α)                                                                piperidinocarbonyl                                                                             1, 9                                             p-MeO-phenyl                                                                              Me.sub.2 NCO     1                                                C.sub.10 H.sub.7 (α)                                                                Me.sub.2 NCO     1, 9                                             C.sub.10 H.sub.7 (α)                                                                n.Pr.sub.2 NCO   9                                                CONMe.sub.2 p-tolyl          1                                                trans-p-MeS-                                                                              Et.sub.2 NCO     1, 9                                             styryl                                                                        Biphenylyl  Et.sub.2 NCO     1, 9                                             trans-p-NCS-                                                                  styryl      Et.sub.2 NCO     2                                                trans-p-MeS-                                                                  styryl      pyrrolidinocarbonyl                                                                            5, 9                                               "         MeEtNCO          1B, 9                                              "         (n-Pr).sub.2 NCO 1B                                               ______________________________________                                    

The anti-viral compounds may be formulated for administration inconjunction, if desired, with one or more pharmaceutical or veterinarycarriers or excipients suitable, for example for oral, topical, rectal,intravaginal or parenteral administration. The pharmaceutical orveterinary composition so formed may include other therapeuticallyeffective compounds, for example antiinflammatory agents such assteroids, e.g. betamethasone-21-phosphate, or antibiotics such astetracycline.

5-Diethylcarbamoyl-3α-naphthyl-1,2,4-oxadiazole and3-biphenylyl-5-diethylcarbamoyl-1,2,4-oxadiazole have been found to beparticularly suitable for formulation for topical administration.

Solid preparations for oral consumption are usually presented in unitdose form and include for instance, tablets, capsules, lozenges, chewinggum and medicated sweets.

Each dosage unit preferably contains 0.05 to 4 g of active antiviralmaterial, advantageously 0.1 to 1.0 g. The material may be administered,for example, 1 to 3 times per day but the total daily dose should be inthe range 0.1 to 7 g. It will be seen from the forgoing table that thecompounds are of particular interest in combatting Rhinovirusinfections.

Conventional carriers for such preparations may be sugars, starches,sugar alcohols, gelatin, chicle gum, cocoa butter, etc., together withother compounding agents required such as binders, lubricants,stabilisers, coatings, flavourings and colourings. The compositions mayalso take the form of liquid oral preparations for ingestion such assolutions, suspensions, syrups, elixirs, emulsions, granules forreconstitution before use, etc., which may contain suspending,emulsifying, stabilising and preserving agents and may also containacceptable sweetening, flavouring or colouring agents. The compounds maybe prepared for local application to the mucous membranes of the noseand throat and may take the form of liquid sprays or powderinsufflations, nasal drops or ointments, throat paints, gargles orsimilar preparations. Topical formulations for the treatment of eyes andears and external applications may be prepared in oily, aqueous orpowdered media in the form of conventional ophthalmic preparations andcollyria, skin paints, lotions, creams, ointments, dusting powders,medicated dressings, eye drops and lotions, etc. Aerosol forms of thepreparations for local application may also be advantageous.Suppositories and pessaries may contain a conventional base e.g. oil oftheobroma, polyglycols, glyco-gelatin bases together with surface activeagents if required. The injectable preparations may take the form ofaqueous or oily solutions, emulsions, suspensions, or solids forreconstitution before use. Suitable vehicles include, for example,sterile, pyrogen-free water, parenterally acceptable oils, oily estersor other non-aqueous media such as propylene glycol if desiredcontaining suspending, dispersing, stabilising, preserving,solubilising, emulsifying or buffering agents.

As stated above, antiparasitic activity has also been shown in the groupof compounds in accordance with the invention, particularly againstEntamoeba histolytica.5-Diethylcarbamoyl-3-p-methylsulphinylstyryl-1,2,4-oxadiazole and5-piperidinocarbonyl-3-trans-p-methylsulphinylstyryl- 1,2,4-oxadiazolehave been shown to be highly active against this parasite. Othercompounds which have shown activity against this parasite are:

5-dimethylcarbamoyl-3-methyl-1,2,4-oxadiazole;

5-methylcarbamoyl-3-methyl-1,2,4-oxadiazole;

5-diethylcarbamoyl-3-p-methoxyphenyl-1,2,4-oxadiazole;

trans-5-diethylcarbamoyl-3-p-methylthiostyryl-1,2,4-oxadiazole;

5-pyrrolidinocarbonyl-3-trans-p-methylsulphinylstyryl-1,2,4-oxadiazole;

5-n-butylcarbamoyl-3-trans-p-methylsulphinylstyryl-1,2,4-oxadiazole;

5-methylcarbamoyl-3-trans-p-methylsulphinylstyryl-1,2,4-oxadiazole;

5-di-n-propylcarbamoyl-3-trans-p-methylsulphinylstyryl-1,2,4-oxadiazole;

5-ethylcarbamoyl-3-trans-p-methylsulphinylstyryl-1,2,4-oxadiazole;

5-N-ethyl-N-methylcarbamoyl-3-trans-p-methylsulphinylstyryl-1,2,4-oxadiazole;

5-piperidinocarbamoyl-3-trans-p-methylthiostyryl-1,2,4-oxadiazole.

Activity has also been shown against the Helminth Nematospiroidesdubius, particularly by 5-dimethylcarbamoyl-3-phenyl-1,2,4-oxadiazole.

Trans-5-diethylcarbamoyl-3-(5-nitrofuryl-2-ylvinyl)-1,2,4-oxadiazole hasalso shown activity against S. aureus, E. coli, B.C.G. S. typhinurium.It has also been found to be active against M. canis.

The compounds may be formulated for antiparasitic and antibacterialadministration by the methods described above. When presented in unitdose form, each dosage unit may generally contain 2-500 mg, preferably2-250 mg, of the active ingredient. The material may be administered ata daily dose of 0.5 to 100 mg/kg, preferably 1-60 mg/kg, and mostconveniently 1-20 mg/kg body weight.

The invention is further illustrated by the following examples. Thepreparation of certain novel starting materials is given as a series ofPreparations. The products of these Preparations are then used in theExamples.

PREPARATION 1 5-Ethoxycarbonyl-3-methyl-1,2,4-oxadiazole

To a stirred suspension of acetamidoxime (3.2g.) in ethanol-freechloroform (25 ml.) containing pyridine (10 ml.) was added ethyl oxalylchloride (8.7 g.) with cooling. The resulting solution was heated underreflux for one hour and then cooled, shaken with 2-N-hydrochloric acid(30 ml), and then water (25 ml.), dried, and evaporated to dryness togive a yellow oil. Distillation under vacuum gave title compound (4.36g.) b.p. 57°-61° at 0.4 mm. ν_(max). (CHBr₃) 1750 cm..sup.⁻¹ (--CO₂ Et).

PREPARATION 2 5-Ethoxycarbonyl-3-α-naphthyl-1,2,4-oxadiazole

A solution of ethoxalyl chloride (24 ml.) in ethanol-free chloroform (25ml.) was added dropwise with cooling during 30 min. to a suspension ofα-naphthylcarbonamidoxime (34.78g.) in ethanol-free chloroform (120 ml.)containing pyridine (30 ml.). The mixture was heated under reflux for 1hr. and cooled. The solution was washed with 2N-hydrochloric acid andwater and then dried. The chloroform solution was evaporated to drynessunder reduced pressure leaving a pale yellow solid which was stirredwith aqueous methanol to give title compound (31.8 g), m.p. 68°-70°,λ_(max). (EtOH) 302 nm (ε 8,420). Similarly was prepared

PREPARATION 3

3-Biphenylyl-5-ethoxycarbonyl-1,2,4-oxadiazole in 98.6% yield, m.p.81°-82° (MeOH), λ_(max). (EtOH) 272 nm (ε 26,400), ν_(max). (CHBr₃) 1750cm..sup.⁻¹ (CO₂ Et).

PREPARATION 4 5-Ethoxycarbonyl-3-trans-p-methylthiostyryl-1,2,4-oxadiazole

Ethoxalyl chloride (8.7 g.) in ethanol-free chloroform (50 ml.) wasadded during 1 hr. to a stirred suspension ofp-methylthiocinnamamidoxime (11.6g.) in chloroform (600 ml.) andpyridine (5.15 ml.) at -3°. After 16 hr. at -20° the solution wasfiltered and refluxed for 1 hr. with azeotropic removal of water. Thesolution was cooled and washed successively with 2N-hydrochloric acid,sodium hydrogen carbonate solution and water. The solution was dried andevaporated. The residue was crystallised from aqueous acetone (charcoal)to give the title compound (12.7 g.), m.p. 88°-89°, λ_(max). (EtOH) 237,326 nm (ε12,400 and 29,500), ν_(max). (CHBr₃) 1752, 1648 and 973cm..sup.⁻¹.

PREPARATION 5 5-Ethoxycarbonyl-3-p-methoxyphenyl-1,2,4-oxadiazole

Ethoxalyl chloride (11 ml.) in ethanol-free chloroform (5.6 ml.) wasadded at 0° over a period of 45 min. to a stirred solution ofp-methoxybenzamidoxime (13.45g.) in chloroform (73 ml.) containingpyridine (6.5 ml.). Stirring was continued at room temperature for afurther 2.5 hr. Chloroform was added and the solution was washedsuccessively with 2N-hydrochloric acid, water, sodium hydrogencarbonate, and water. Evaporation left a residue which waschromatographed on silica (1 kg.) in benzeneethyl acetate (9:1 v/v) togive the oxadiazole as an oil (11.73g.) which slowly crystallised.Recrystallisation from aqueous acetone gave the title compound, m.p.59°-60°, λ_(max). (EtOH) 252 nm (ε 21,200).

PREPARATION 6 3-trans-p-Chlorostyryl-5-ethoxycarbonyl-1,2,4-oxadiazole

p-Chlorocinnamamidoxime (anhydrous, 25.74g.) was dissolved in chloroform(300 ml.) containing pyridine (10.34g.). Ethyl oxalyl chloride (16.5g.)in chloroform (15 ml.) was added dropwise, with stirring. Stirring wascontinued for 1 hr., then the mixture was filtered and the filtrate wasevaporated to dryness under reduced pressure. The residue wasrecrystallised from aqueous ethanol to give title compound (9.76 g.),m.p. 94°-95°. λ_(max). (EtOH) 228, 285,nm. (ε 12,990, 31,450) ν_(max).(CHBr₃) 975 cm..sup.⁻¹ (trans-CH=CH).

PREPARATION 7 3,5-Bis-ethoxycarbonyl-1,2,4-oxadiazole

Ethyl oxalyl chloride (10 ml.) was added dropwise, with cooling, to asolution of ethoxycarbonyl-formamidoxime (10g.) in ethanol-freechloroform (100 ml.) containing pyridine (10 ml.). The mixture washeated under reflux for 1 hr., cooled and washed with 2N-hydrochloricacid (50 ml.) and water (50 ml.) and dried. Evaporation gave titlecompound (6.5 g.), n_(D) ²¹ 1.4571.

PREPARATION 8 5-Hydrazinocarbonyl-3-α-naphthyl-1,2,4-oxadiazole

5-Ethoxycarbonyl-3-α-naphthyl-1,2,4-oxadiazole (10.0g.) was dissolved inmethanol (150 ml.) and hydrazine hydrate (10.0g.) added dropwise withcooling. The mixture was stirred for fifteen minutes and the crystallineprecipitate was filtered off, washed with methanol (10 ml.), and driedto give title compound (7.08 g), m.p. 211°-212° (decomp.) λ_(max).(EtOH) 302 nm (ε 10,100) ν_(max). (Nujol) 1680 cm..sup.⁻¹ (--CONH--).

Similarly were prepared

PREPARATION 9

5-Hydrazinocarbonyl-3-methyl-1,2,4-oxadiazole in 54.7% yield, m.p.150°-151°, ν_(max). (Nujol) 1672 cm..sup.⁻¹ (--CONH--).

PREPARATION 10

trans-5-Hydrazinocarbonyl-3-p-methylthiostyryl-1,2,4-oxadiazole in 92.4%yield, m.p. 207° (decomp.) λ_(max). (EtOH) 238, 326 nm. (ε 15,300,31,000) ν_(max). (Nujol) 1670 cm..sup.⁻¹ (--CONH--) τ (d⁶ DMSO) 7.47(CH₃ S--) 2.73 (doublet, J 16 Hz.) and 2.24 (doublet, J 16 Hz.) -CH=CH-(trans).

PREPARATION 11 5-Azidocarbonyl-3-α-naphthyl-1,2,4-oxadiazole

5-Hydrazinocarbonyl-3-α-naphthyl-1,2,4-oxadiazole (6.47g.) was dissolvedin acetic acid (125 ml.) and 2N-hydrochloric acid (75 ml.). A solutionof sodium nitrite (2.0g) in water (6 ml.) as added at 0° with stirring.After 15 minutes the precipitate was filtered off and dissolved inchloroform. The chloroform solution was washed with water and dried(MgSO₄). Evaporation to dryness gave title compound (5.82 g.), m.p. 114°(decomp.), λ_(max). (EtOH) 300 nm. (ε 8,250), ν_(max). (CHBr₃) 1710(C=O), 2150 and 2190 cm..sup.⁻¹ (N₃).

Similarly were prepared

PREPARATION 12

trans-5-Azidocarbonyl-3-p-methylthiostyryl-1,2,4-oxadiazole in 73.7%yield, m.p. 125° (decomp.) λ_(max). (EtOH) 237, 325 nm. (ε 12,400,24,300), λ_(max). (CHBr₃) 1715 (C=O), 2160 and 2202 cm..sup.⁻¹ (N₃), τ(d₆ -DMSO) values include 2.21 (doublet J 16 Hz) and 2.68 (doublet J 16Hz, trans CH=CH).

PREPARATION 13

5-Azidocarbonyl-3-methyl-1,2,4-oxadiazole in 33.4% yield, m.p. 71°-72°,ν_(max). (CHBr₃) 1710 (C=O), 2150 and 2192 cm..sup.⁻¹ (N₃).

PREPARATION 14

3-Ethoxycarbonyl-5-p-tolyl-1,2,4-oxadiazole

Ethoxycarbonylformamidoxime (46.0g.) was stirred in chloroform (450 ml.)and pyridine (32.5 ml.) and a solution of p-tolyl chloride (54g.) inchloroform (50 ml.) was added during 1 hr. and stirring was continuedfor a further 1 hr. The solid that separated was filtered off and washedwith water to give the O-acylated amidoxime (63.5g., 72%), m.p.188°-190°. Part of this product (5.0g.) was heated under reflux inxylene (100 ml.) for 4 hr. with azeotropic removal of water; the xylenewas then removed under reduced pressure. The residue was recrystallisedfrom aqueous methanol to give the title compound (4.4g.), m.p. 76°-77°,λ_(max). (EtOH) 263 nm. (ε 19,620) ν_(max). (CHBr₃) 1750, 1210cm..sup.⁻¹ (CO₂ Et).

PREPARATION 15 5-p-Chlorophenyl-3-ethoxycarbonyl-1,2,4-oxadiazole

p-Chlorobenzoyl chloride (9.5g.) in chloroform (20 ml.) was addeddropwise to a stirred solution of ethoxycarbonylformamidoxime (7.21g.)in chloroform (60 ml.) and pyridine (18 ml.). After 1 hr. the solid(12.32g.) was filtered off and washed with chloroform. Some of thissolid (10.0 g.) was heated under reflux in xylene (250 ml.) for 20 hr.,with azeotropic removal of water. The xylene was removed under reducedpressure, and the residue was recrystallised from ethanol to give titlecompound (8.11 g.), m.p. 93.5°, λ_(max). (EtOH) 261-262 nm. (ε 2,540),ν_(max). (CHBr₃) 1745 and 1210 cm..sup.⁻¹ (CO₂ Et). The followingcompounds were similarly prepared:

PREPARATION 16

3-Ethoxycarbonyl-5-p-nitrophenyl-1,2,4-oxadiazole in 88% yield, m.p.144°-145°, λ_(max)..sup. (EtOH) 274 nm (ε 21,200) ν_(max). (CHBr₃)1750and 1218 (CO₂ Et), 1536 and 1350 cm..sup.⁻¹ (NO₂).

PREPARATION 17

3-Ethoxycarbonyl-5-(2-thienyl)-1,2,4-oxadiazole in 43% yield, m.p. 76°,λ_(max)..sup. (EtOH) 263-264, 289 nm, (ε10,960, 16,280), ν_(max).(CHBr₃) 1210 and 1745 cm..sup.⁻¹ (CO₂ Et).

PREPARATION 18 3-Ethoxycarbonyl-1,2,4-oxadiazole

Ethoxycarbonylformamidoxime (39.6g., 300 mmole) was added to triethylorthoformate (180 ml.) containing boron trifluoride etherate (0.9 ml.),and the solution was heated under reflux for 1 hr., then cooled andfiltered. The filtrate was evaporated to dryness under reduced pressureand the residue, dissolved in chloroform was washed with 2N-hydrochloricacid, then with saturated sodium hydrogen carbonate solution and dried(MgSO₄). Removal of the solvent left an oil (37.2g.) which partiallycrystallised. The residual oil was sucked off, leaving the oxadiazole,(33.94g), m.p. 41°-43°, b.p. 80°-90° (bath)/0.6 mm.

PREPARATION 19 3-Hydrazidocarbonyl-1,2,4-oxadiazole

Hydrazine hydrate (98%, 3.15 ml.) was added at <15° in 3 portions during20 min. to a stirred solution of 3-ethoxycarbonyl-1,2,4-oxadiazole (5.96g.) in dry ethanol (29 ml.). The mixture was stirred for 50 min. at 0°and then filtered, to give title compound 5.26 g., m.p. 112° (decomp.)λ_(max). 242-243 nm (ε 3,950).

PREPARATION 20 3-Azidocarbonyl-1,2,4-oxadiazole

Sodium nitrite (2.70g.) in water (7.5 ml.) was added, at 0°, withstirring, during 40 min., to a solution of3-hydrazidocarbonyl-1,2,4-oxadiazole (4.48 g.) in 2N-hydrochloric acid(50 ml.) and glacial acetic acid (20 ml.). After 1 hr., water was addedand the product was extracted into chloroform Evaporation of the solventand removal of residual acetic acid under vacuum gave the azide, (3.17g), m.p. 89°-90°, λ_(max). (EtOH) 241 nm (ε 4,580).

PREPARATION 21 3-Chlorocarbonyl-1,2,4-oxadiazole

Dry hydrogen chloride was passed for 2 hr. through a solution of3-hydrazidocarbonyl-1,2,4-oxadiazole (11.96g., 93.7 mmole) in drymethanol (630 ml.), then the solution was evaporated to dryness. Drynitromethane (30 ml.) was added and the evaporation was repeated. Theresidue was dissolved in nitromethane (200 ml.) and hydrogen chloridewas again passed into the solution for 45 min. Chlorine was then passedin for 1 hr., when the evolution of nitrogen ceased. The residualchlorine was removed by the passage of nitrogen, the suspension wasfiltered, and the filtrate was evaporated to give the crude acidchloride, 10.2 g. Distillation gave title compound b.p. 47-47.5°/2.5 mm.ν_(max). (CS₂) 1785 (COCl), 3130 cm..sup.⁻¹ (CH).

PREPARATION 22 5-Ethoxycarbonyl-3-α-naphthyl-1,2,4-oxadiazole

α-Naphthylcarbonamidoxime (149.5 g.) was suspended in dry ethyl acetate(510 ml.) and propylene oxide (153 ml.). A solution of ethyl oxalylchloride (97 ml.) in dry ethyl acetate (100 ml.) was added to thestirred suspension at 0° to 5° during 1 hour. The solution was stirredat room temperature for 30 minutes and then heated under reflux for 2hours. The cooled solution was washed with 2N-sodium carbonate solutionand water and dried over sodium sulphate. Removal of the solvent underreduced pressure gave a brown oil (237.9 g.) which was vigorouslystirred with methanol-water (7:1, v/v) (131 ml.), and dried to give theester (193.1 g., 89.7%), m.p. 72°-73°.

PREPARATION 23 5-Ethoxycarbonyl-3-p-methoxystyryl-1,2,4-oxadiazole

p-Methoxycinnamamidoxime (1.25 g.) was stirred in dry ethyl acetate (20ml.) and propylene oxide (0.9 ml.) was added. A solution of ethyl oxalylchloride (0.84 ml.) in ethyl acetate (5 ml.) was added dropwise, withstirring, during 30 minutes at 0°-5°. The suspension was allowed to warmto 18° and was then heated under reflux for 90 minutes. The solution wascooled, washed with 2N-sodium carbonate solution and with water, driedand treated with charcoal. Removal of the solvent and recrystallisationfrom methanol gave the oxadiazole (1.534 g., 86%), m.p. 115°-116°,λ_(max). (EtOH) 225.5, 300 (infl.), and 308.5 nm (ε 14500, 26000 and26600), ν_(max). (CHBr₃) 820 (C₆ H₄) 970 (trans-CH=CH), 1752 (C=O),cm..sup.⁻¹.

PREPARATION 24trans-5-Ethoxycarbonyl-3-(5-nitrofur-2-ylvinyl)-1,2,4-oxadiazole

trans-5-Nitrofur-2-ylacrylamidoxime (2.0 g.) was suspended inethanol-free chloroform (40 ml.) containing pyridine (1.6 ml.).Ethoxalyl chloride (2.5 ml.) was added dropwise and the mixture washeated under reflux for 2 hours. After cooling the reaction mixture waspoured into water (100 ml.) and extracted with chloroform (100 ml.). Thedried (MgSO4) extract was evaporated to dryness and the residue wascrystallised from methanol (90 ml.) to give the title compound (2.3 g.,80%), m.p. 138°-139°, ν_(max). (CHBr₃) 1755 (CO₂ Et), 1508 and 1350(NO₂), 959 cm..sup.⁻¹ (trans CH=CH).

PREPARATION 25 3-Benzyl-5-ethoxycarbonyl-1,2,4-oxadiazole

Ethoxalyl chloride (1.75 ml.) in dry ethylacetate (10 ml.) was added at0°-5° during 10 minutes to a stirred solution of phenylacetamidoxime(1.5 g.) in ethylacetate (10 ml.). After stirring at room temperaturefor 90 minutes the mixture was heated under reflux for 21/2 hours. Thesolution was washed with 2N-sodium carbonate and water, dried andevaporated to give a yellow oil which was chromatographed on silica (100g.). Elution with benzene/ethylacetate (3:1) gave the oxadiazole (2.25g.) which was subsequently distilled, b.p. 170°-180° at 1.3 mm ν_(max).(CHBr₃) 1750 cm¹¹⁶ 1 (ester).

EXAMPLE 1 5-Diethylcarbamoyl-3-α-naphthyl-1,2,4-oxadiazole.

5-Ethoxycarbonyl-3-α-naphthyl-1,2,4-oxadiazole (30.9 g.) was heatedunder reflux in an excess of diethylamine (35.6g.) for 1.5 hr. Themixture was cooled and evaporated under reduced pressure to give a solidwhich was recrystallised from methanol yielding title compound (29.3g.), m.p. 101.5°-102.5°, λ_(max). (EtOH) 302 nm. (ε 9,700), ν_(max).(CHBr₃) 1662 cm..sup.⁻¹ (CONEt₂).

EXAMPLE 2 trans-5-Diethylcarbamoyl-3-p-methylthiostyryl-1,2,4-oxadiazole

trans-5-Ethoxycarbonyl-3-p-methylthiostyryl-1,2,4-oxadiazole (600 mg.)was heated to reflux for 30 min. in an ethanolic solution ofdimethylamine (10 ml.). The reaction mixture was evaporated to drynessand the solid residue was recrystallised from methanol (8 ml.) to givetitle compound (544 mg.), m.p. 119°-120°, λ_(max). (EtOH) 238, 315(inflection), 327 nm. (ε 15,800; 26,000, 30,950) ν_(max). (CHBr₃) 1668(--CONMe₂) and 978 cm..sup.⁻¹ (trans CH=CH).

EXAMPLE 3 trans-5-Diethylcarbamoyl-3-p-methylthiostyryl-1,2,4-oxadiazole

trans-5-Ethoxycarbonyl-3-p-methylthiostyryl-1,2,4-oxadiazole (13.3g.)was heated under reflux with a mixture of diethylamine (80 ml.) andmethanol (20 ml.) for 1 hr. The cooled reaction mixture was evaporatedand the residue was recrystallised from aqueous methanol to give thetitle amide (11.5 g.), m.p. 78°-79°, λ_(max)..sup.(EtOH) 237, 311(inflection), 326 nm (ε 16,100; 23,000, 32,000) ν_(max). (CHBr₃) 1663(CONEt₂) and 972 cm..sup.⁻¹ (trans CH=CH).

EXAMPLE 4 5-Dimethylcarbamoyl-3-α-naphthyl-1,2,4-oxadiazole

5-Ethoxycarbonyl-3-α-naphthyl-1,2,4-oxadiazole (618 mg.) was dissolvedin an ethanolic solution of dimethylamine (10 ml., 33% v/v). After 1 hr.The solution was evaporated leaving a residue that was recrystallisedfrom methanol (3.5 ml.) to give title compound (424 mg.,) m.p.109°-110°, λ_(max). (EtOH) 302.5 nm (ε 9,400) ν_(max). (CHBr₃) 1660cm..sup.⁻¹ (CONMe₂).

EXAMPLE 5 3-Adamant-1-ylcarbamoyl-1,2,4-oxadiazole.

3-Azidocarbonyl-1,2,4-oxadiazole (350 mg.) was added to a solution of1-aminoadamantane (378 mg.) in chloroform (15 ml.) and the mixture wasstirred for 24 hr. The chloroform solution was evaporated to drynessunder reduced pressure and the residue was recrystallised from aqueousmethanol to give title compound (167 mg.), m.p. 141°-142°, ν_(max).(EtOH) 230 nm (ε 3,910), λ_(max). (Nujol) 3392 (--NH--) 1692 and 1515cm..sup.⁻¹ (CONH). Further examples provided in Table II were preparedby the following general methods:

Method A

The appropriate 3- or 5-alkoxycarbonyl-1,2,4-oxadiazole was treated withan excess of the primary or secondary amine (1-10 equivs.) at a suitabletemperature, between room temperature and the boiling point. Excessamine was removed under reduced pressure and the product wasrecrystallised.

Method B

Similar to Method A except that a solvent such as ethanol or methanolwas used as diluent.

Method C

The appropriate 3- or 5-azidocarbonyl-1,2,4-oxadiazole was treated withthe primary or secondary amine (1-2 equivs.) at room temperature in asuitable solvent (e.g. chloroform) and the product isolated byevaporation and recrystallisation.

Method D

Similar to Method C except that the 3- aor5-chlorocarbonyl-1,2,4-oxadiazole was used to acylate the amine.

Examples 6-40 and 52-60 refer to the formula ##SPC5##

Examples 41-51 refer to the formula ##SPC6##

                                      Table II                                    __________________________________________________________________________                                              λ  νmax.                                                            max.      (--CON<)                  Ex.                              Cryst.                                                                             M.p.                                                                              nm.       cm..sup.-.sup.1                                                                      Yield              No.                                                                              R.sup.1       R.sup.2    Method                                                                             Solvent                                                                            ° C                                                                        (EtOH)                                                                             ε                                                                          (CHBr.sub.3)                                                                         %                  __________________________________________________________________________    6  Ph            N(CH.sub.3).sub.2                                                                        B    MeOH 79- 244  7,300                                                                              1678   67                                             (EtOH)    81°    (CS.sub.2)                7  Ph            NHCH.sub.3 B    MeOH 114-                                                                              --   --   1715   56                                             (EtOH)    115           (CS.sub.2)                8  Ph            N(C.sub.2 H.sub.5).sub.2                                                                 A    petrol                                                                             45- --   --   1660   71                                                  (40- 46                                                                       60°)                                  9  Ph            NHC.sub.2 H.sub.5                                                                        A    EtOH/                                                                              89- --   --   1700   79                                                  petrol                                                                             90                                                                       (40-                                                                          60°)                                  10 CH.sub.3       N(CH.sub.3).sub.2                                                                       B    MeOH/                                                                              35- --   --   1660   70                                             (MeOH)                                                                             petrol                                                                             37                                                                       (60-                                                                          80°)                                  11 Ph            NHPh       C    MeOH/                                                                              110-                                                                              --   --   1710   72                                                  petrol                                                                             112                                                                      (80-                                                                          100°)                                 12 Ph            N(CH.sub.3)Ph                                                                            C    "    83- --   --   1662   63                                                       85                                      13 CH.sub.3      NHCH.sub.3 B    benzene                                                                            99- --   --   1658   48                                             (MeOH)    101                                     14 Ph                                                                                           ##STR2##  A    EtOH 138- 140                                                                          231  18,000                                                                             1650   60                 15 Ph                                                                                           ##STR3##  A    EtOH 66- 67.5                                                                          235  17,000                                                                             1660   47                 16 Ph                                                                                           ##STR4##  A    Et.sub.2 O                                                                         81- 83                                                                            224  18,300                                                                             1655   49                 17 Ph                                                                                           ##STR5##  A    EtOH 82- 83                                                                            235  15,300                                                                             1658   82                 18                                                                                ##STR6##     N(C.sub.2 H.sub.5).sub.2                                                                 A    EtOH 62- 63                                                                            256.5                                                                              19,360                                                                             1643   35                 19                                                                                ##STR7##                                                                                    ##STR8##  A    MeOH/ H.sub.2 O                                                                    78- 79                                                                            258  19,660                                                                             1656   43                 20                                                                                ##STR9##     N(CH.sub.3).sub.2                                                                        B (EtOH)                                                                           EtOH 123- 124                                                                          256  19,600                                                                             1665   81                 21 αC.sub.10 H.sub.7                                                                      ##STR10## A    MeOH/ H.sub.2 O                                                                    107- 108                                                                          302.5                                                                              10,260                                                                             1655   55                 22 αC.sub.10 H.sub.7                                                                     N(CH.sub.3).sub.2                                                                        B    MeOH 109-                                                                              302.5                                                                              9,370                                                                              1660   68                                             (EtOH)    110                                     23 αC.sub.10 H.sub.7                                                                     N(C.sub.3 H.sub.7).sub.2                                                                 A    MeOH 41.5-                                                                             302.5                                                                              10,350                                                                             1658   52                                                       43                                      24 αC.sub.10 H.sub.7                                                                     N(CH.sub.3)Ph                                                                            C    MeOH 88- 293  8,900                                                                              1670   40                                                       89                                      25 αC.sub.10 H.sub.7                                                                     N(C.sub.4 H.sub.9).sub.2                                                                 C    --   oil 302  7,450                                                                              1650   78                 26 (C.sub.2 H.sub.5).sub.2 NCO                                                                 N(C.sub.2 H.sub.5).sub.2                                                                 A    MeOH 55- 235 inf.                                                                           6,030                                                                              1660   55                                                       56                                      27                                                                                ##STR11##    N(C.sub. 2 H.sub.5).sub.2                                                                A    MeOH 81- 82                                                                            275.5                                                                              28,100                                                                             1660   72                 28                                                                                ##STR12##                                                                                   ##STR13## C    EtOH 130- 131                                                                          (238 (327                                                                          16,800) 30,600)                                                                    1700   71.5               29 αC.sub.10 H.sub.7                                                                      ##STR14## C    MeOH/ H.sub.2 O                                                                    64- 65                                                                            302  8,590                                                                              1696   81                 30                                                                                ##STR15##    NHC.sub.4 H.sub.9                                                                        A    MeOH 105- 106                                                                          (237 (326                                                                          17,300) 30,500)                                                                    1692   57                 31                                                                                ##STR16##    N(C.sub.2 H.sub.5).sub.2                                                                 A    MeOH 73- 74                                                                            (221 (227 (285                                                                     18,700) 16,100) 31,900                                                             1660   87                 32                                                                                ##STR17##    A          MeOH 115- 116                                                                           (220 (227.5                                                                       18,900) 15,400)                                                                    1660 80                        33 CH.sub.3                                                                                     ##STR18## C    --   86- 88                                                                            234  6,110                                                                              1700   65                 34 αC.sub.10 H.sub.7                                                                      ##STR19## C    MeOH 120- 121                                                                          302  9,480                                                                              1662   59                 35                                                                                ##STR20##    NHC(CH.sub.3).sub.3                                                                      A    MeOH 113- 114                                                                          (235.5 (325                                                                        16,800)  30,400)                                                                   1702   67                 36                                                                                ##STR21##    N(C.sub.2 H.sub.5).sub.2                                                                 A    MeOH 84- 85                                                                            (226 (246 (322                                                                     38,900) 25,500) 15,300                                                             1665   67                 37 αC.sub.10 H.sub.7                                                                     N(CH.sub.2 CH.sub.2 OH).sub.2                                                            B    MeOH 118-                                                                              301.5                                                                              9,300                                                                              1662   66                                                       119                                     38 αC.sub.10 H.sub.7                                                                      ##STR22## B    MeOH 119- 120                                                                          302.5                                                                              8810 1695   75                 39 αC.sub.10 H.sub.7                                                                     NHCH.sub.2 CH                                                                            B    EtOH 105-                                                                              302.5                                                                              8700 1700   74                                  CH.sub.2             106                                     40 PhCH.sub.2    N(C.sub.2 H.sub.5).sub.2                                                                 A    --   Oil 253.5                                                                              2200 1662   100                41 (CH.sub.3).sub.2 N                                                                          CH.sub.3   B    --   liquid                                                                            --   --   1660   48                                             (MeOH)                                            42 CH.sub.3 NH   CH.sub.3   B    MeOH/                                                                              109-                                                                              --   --   1700   74                                             (MeOH)                                                                             petrol                                                                             110                                                                      (40-                                                                          60°)                                  43 (CH.sub.3).sub.2 N                                                                          Ph         C    CHCl.sub.3 /                                                                       80- --   --   1658   78                                                  petrol                                                                             81                                                                       60-                                                                           80°                                   44 (C.sub.2 H.sub.5).sub.2 N                                                                   Ph         A    --   liquid                                                                            --   --   1640   68                 45                                                                                ##STR23##    H          C,D  --   156- 157                                                                          271.5                                                                              11,300                                                                             1710   77, 97             46 (CH.sub.3).sub.2 N                                                                           ##STR24## B (MeOH)                                                                           MeOH/ H.sub.2 O                                                                    97- 99                                                                            260  28,200                                                                             1650   65                 47 (CH.sub.3).sub.2 N                                                                          αC.sub.10 H.sub.7                                                                  B    MeOH/                                                                              109-                                                                              239) 312)                                                                          27,600 1700                                                                        1652   70                                             (MeOH)                                                                             H.sub.2 O                                                                          110                                     48 (CH.sub.3).sub.2 N                                                                           ##STR25## B (MeOH)                                                                           MeOH/ H.sub.2 O                                                                    113- 114                                                                          287  17,500                                                                             1650   72                 49 (C.sub.2 H.sub.5).sub.2 N                                                                    ##STR26## B (CHCl.sub.3)                                                                     MeOH/ H.sub.2 O                                                                    119- 120                                                                          274  19,400                                                                             1645   35                 50 (CH.sub.3).sub.2 N                                                                           ##STR27## B (MeOH)                                                                           MeOH 58- 59                                                                            262  30,900                                                                             1660   58                 51                                                                                ##STR28##    H          C    MeOH/ H.sub. 2 O                                                                   128- 129                                                                          --   --   1650   73                 52                                                                                ##STR29##                                                                                   ##STR30## B    aqueous methanol                                                                   117- 118                                                                          237.5 327                                                                          17,000 30,000                                                                      1650   87                 53 "                                                                                            ##STR31## B    ethanol                                                                            137- 139                                                                          237 326.5                                                                          15,900 30,600                                                                      1660   93                 54 "                                                                                            ##STR32## B    methanol                                                                           122- 123                                                                          236.5 326.5                                                                        16,300 30,000                                                                      1660   93                 55 "                                                                                            ##STR33## B    aqueous  acetone                                                                   Ca. 45                                                                            236.5 327                                                                          16,500 29,900                                                                      1660   85                 56 "             NH CH.sub.3                                                                              B    ethanol                                                                            200-                                                                              235  16,800                                                                             1708   84                                                       202 326  29,200                         57 "             NHC.sub.2 H.sub.5                                                                        B    aqueous                                                                            123-                                                                              236  17,500                                                                             1704   87                                                  methanol                                                                           124 326  28,900                         58 "             N(CH.sub.3)C.sub.2 H.sub.5                                                               B    methanol                                                                           74- 236  15,600                                                                             1665   77                                                       76  326  30,000                         59 "             N[C.sub.3 H.sub.7(n) ].sub.2                                                             B    methanol                                                                           58- 237  16000                                                                              1652   56                                                       59  326  32,000                         60 "             NHC.sub.4 H.sub.9 (n)                                                                    B    aqueous                                                                            110-                                                                              236 326                                                                            17,200 29,200                                                                      1700   96                                                  methanol                                                                           111                                     __________________________________________________________________________

EXAMPLE 615-Diethylcarbamoyl-3-trans-p-methylsulphinylstyryl-1,2,4-oxadiazole.

Peracetic acid (1 ml., comml. ca. 40%) was extracted with methylenechloride (5 ml.) and a portion (3.5 ml.) of this extract was addeddropwise at room temperature to a stirred solution of5-diethylcarbamoyl-3-trans-p-methylthiostyryl-1,2,4-oxadiazole (1.00g)in methylene chloride (50 ml.) during 70 minutes. The solution wasshaken with saturated sodium hydrogen carbonate solution (20 ml), andthen water (20 ml), and dried Removal of the solvent reduced pressuregave an off-white solid which was stirred with petroleum (50 ml, b.p.40°-60°), filtered off and dried under vacuum to give title compound(1.00 g.), m.p. 101.5°-102°, λ_(max). (EtOH) 288.5 nm (ε 32,000),ν_(max). (CHBr₃) 1650 (CONEt₂) and 970 cm..sup.⁻¹ (trans CH=CH), τ(CDCl₃) values include 2.19, 2.82 (quartet J 16.5 Hz, trans CH=CH) and7.25 (SOMe).

EXAMPLE 625-Diethylcarbamoyl-3-trans-p-methylsulphonylstyryl-1,2,4-oxadiazole

Peracetic acid (3 ml. comml. ca. 40%) was extracted with methylenechloride (15 ml) and a portion (9.0 ml) of this extract was addeddropwise at room temperature to a stirred solution of5-diethylcarbamoyl-3-trans-p-methylthiostyryl-1,2,4-oxadiazole (0.961g.)in methylene chloride (50 ml.) during 100 minutes. The solution wasshaken with saturated sodium hydrogen carbonate solution (30 ml), andthen water (20 ml), and dried Removal of the solvent under reducedpressure gave title compound (1.01 g.), m.p. 123°-124°, λ_(max). (EtOH)284.5nm (ε34,900), ν_(max). (CHBr₃) 1650 (CONEt₂) and 952 cm..sup.⁻¹(trans CH=CH), τ (CDCl₃) values include 2.17, 2.77 (quartet J 16.5, Hz,trans CH=CH) and 6.90 (SO₂ Me).

EXAMPLE 635-Dimethylcarbamoyl-3-p-methylsulphinylstyryl-1,2,4-oxadiazole

5-Dimethylcarbamoyl-3-p-methylthiostyryl-1,2,4-oxadiazole (700 mg.) wasdissolved in methylene chloride (40 ml.). A solution of ca. 40%peracetic acid in methylene chloride (6.7% w/v; 2.8 ml.) was addeddropwise at room temperature; the reaction was followed by thin-layerchromatography. The solvent was removed under reduced pressure and theresidual solid was stirred with light petroleum (b.p. 40°-60°), leavingthe sulphoxide (670 mg., 90.7%), m.p. 136°-137°. A sample recrystallisedfrom toluene had m.p. 137°-138°, λ_(max). (EtOH) 226, 288.5, and 305 nm,(ε13900, 33200, and 21500) ν_(max). (CHBr₃) 317 (C₆ H₄). 972(trans-CH=CH), 1043 (S → 0), 1660 cm.sup.⁻¹ (CON<).

EXAMPLE 64 5-Diethylcarbamoyl-3-p-methoxystyryl-1,2,4-oxadiazole

5-Ethoxycarbonyl-3-p-methoxystyryl-1,2,4-oxadiazole (1.25 g.) wassuspended in dry methanol (5 ml.) and diethylamine (7.25 ml.) was added.The mixture was heated under reflux for 1 hour, when a solution wasobtained. The solvent was removed under reduced pressure and theresidual oil was dissolved in methanol and treated with charcoal.Evaporation of the filtrate left an oil, which was recrystallised fromaqueous methanol to give the amide (1.199 g., 87.4%), m.p. 69°-70°,λ_(max). (EtOH) 225.5 300 (infl.) and 308 nm. (ε15400, 24400 and 25000),ε_(max). (CHBr₃) 820 (C₆ H₄), 970 (trans-CH=CH), 1650 (CO.N<),

EXAMPLE 65trans-5-Diethylcarbamoyl-3-(5-nitrofur-2-ylvinyl)-1,2,4-oxadiazole

trans-5-Ethoxycarbonyl-3-(5-nitrofur-2-ylvinyl)-1,2,4-oxadiazole (332mg.) was heated under reflux with diethylamine (5 ml.) for 30 min. togive a deep red solution. Evaporation gave a red solid;recrystallisation from methanol (3 ml.) gavetrans-5-diethylcarbamoyl-3-(5-nitrofur-2-ylvinyl)1,2,4-oxadiazole (208mg., 57%), m.p. 118°-119°, λ_(max). (EtOH) 240 and 349 nm. (ε18,600 and19,900), ν_(max). (CHBr₃) 1665 (CONEt₂), 1510, 1352 (NO₂) and 960cm..sup.⁻¹ (trans CH=CH).

EXAMPLE 66

The following compounds were prepared as described in Example 63.

3-trans-p-methylsulphinylstyryl-5-pyrrolidinocarbonyl-1,2,4-oxadiazole

74% yield, m.p. 162°-163° (from toluene-light petroleum b.p. 80°-100°),λ_(max) (EtOH) 289.5 and 305 nm (ε31,900 and 21,400), ν_(max). (CHBr₃)812 (p-C₆ H₄), 970 (trans-CH=CH), 1041 (S→O), 1655 cm.sup.⁻¹ (CON<).

3-trans-p-methylsulphinylstyryl-5-piperidinocarbonyl-1,2,4-oxadiazole

73% yield, m.p. 95°-96° (from toluene-light petroleum, b.p. 80°-100°),λ_(max). (EtOH) 288.5 nm (ε21,200), ν_(max). (CHBr₃) 812 (p-C₆ H₄), 9701(trans-CH=CH), 1041 (S→O), 1660 cm.sup.⁻¹ (CON<).

5-Methylcarbamoyl-3-trans-p-methylsulphinylstyryl-1,2,4-oxadiazole

76% yield, m.p. 193°-194° (from toluene-ethanol), λ_(max). (EtOH) 288.5nm (ε 31,600), ν_(max). (Nujol) 818 (p-C₆ H₄), 969 (trans-CH=CH), 1030(S→O), 1680 cm.sup.⁻¹ (CONH).

5-Ethylcarbamoyl-3-trans-p-methylsulphinylstyryl-1,2,4-oxadiazole

73% yield, m.p. 147°-148° (from toluene-ethanol), λ_(max). (EtOH) 288 nm(ε 32,800), ν_(max). (CHBr₃) 811 (p-C₆ H₄), 970 (trans-CH=CH), 1040(S→O), 1648 cm.sup.⁻¹ (CONH).

5n-Butylcarbamoyl-3-trans-p-methylsulphinylstyryl-1,2,4-oxadiazole

83% yield, m.p. 130°-131° (from toluene-light petroleum, b.p. 80°-100°),λ_(max) (EtOH) 288.5 nm (ε 32,300), ν_(max). (CHBr₃) 812 (p-C₆ H₄), 970(trans-(CH=CH), 1040 (S→O), 1624 cm.sup.⁻¹ (CONH).

5-N-Ethyl-N-methylcarbamoyl-3-trans-p-methylsulphinylstyryl-1,2,4-oxadiazol

86.5% yield, m.p. 109° (from toluene), λ_(max). (EtOH) 288.5 nm (ε34,500) ν_(max). (CHBr₃) 820 (p-C₆ H₄), 978 (trans-CH=CH), 1050 (S→O),1670 cm.sup.⁻¹ (CON<).

3-trans-p-Methylsulphinylstyryl-5-di-n-propylcarbamoyl-1,2,4-oxadiazole.

66% yield, liquid (from aqueous methanol), λ_(max). (EtOH) 289 nm (ε28,200), ν_(max). (CHBr₃) 818 (p-C₆ H₄), 977 (trans-CH=CH), 1050 (S→O),1670 cm.sup.⁻¹ (CON<).

EXAMPLE 675-Diethylcarbamoyl-3-trans-p-thiocyanatostyryl-1,2,4-oxadiazole

3-trans-p-Aminostyryl-5-diethylcarbamoyl-1,2,4-oxadiazole (1.42 g) wasdissolved in glacial acetic acid (30 ml) and 2N-sulphuric acid (10 ml).The solution was stirred, and sodium nitrite (400 mg) in water (10 ml)was slowly added at <5°. The diazonium solution was added dropwise at 0°to a stirred aqueous solution of cuprous thiocyanate (1.5 g) andpotassium thiocyanate (15 g). The mixture was allowed to warm to roomtemperature and the pH was adjusted to 7 (NaHCO₃). The solid thatseparated was extracted into chloroform. The filtered chloroformsolution was washed with sodium hydrogen carbonate solution and withwater, dried (Na₂ SO₄) and evaporated, leaving an oil, which slowlycrystallised. The crystals were washed with a little methanol, givingthe thiocyanate compound (700 mg, 43%), m.p. 97°, λ_(max). (EtOH) 291.5nm (ν 29,000), 223 nm (ε 15,400) ν_(max). (CHBr₃) 1662 (--CON<), 972(trans-CH=CH), 814 (p-C₆ H₄), 2180 cm.sup.⁻¹ (SCN).

The starting material for the above transformation was prepared fromp-nitrocinnamamidoxime by the following sequence

5-Ethoxycarbonyl-3-trans-p-nitrostyryl-1,2,4-oxadiazole.

p-Nitrocinnamamidoxime (17.06 g) was stirred in ethyl acetate (1 l)containing propylene oxide (8.8 ml, 9.63 g). Ethyl oxalyl chloride (16.9ml, 13.6 g) was added dropwise during 45 min. The solution was refluxedfor 1.5 hr, cooled, and washed with 2N-sodium carbonate, then withwater, dried (Na₂ SO₄), and treated with charcoal. The filtered solutionwas evaporated under reduced pressure and the residue was recrystallisedfrom toluene to give the ester (14.02 g; 59%), m.p. 145°, λ_(max).(EtOH) 308.5nm (ε 22,800), λ_(infl). 228 nm (ε 11,800), ν_(max). (CHBr₃)1525 and 1348 (NO₂), 1753 (CO₂ Et), 835 (p-C₆ H₄), 972 cm.sup.⁻¹(trans-CH=CH).

5-Diethylcarbamoyl-3-trans-p-nitrostyryl-1,2,4-oxadiazole

5-Ethoxycarbamoyl-3-trans-p-nitrostyryl-1,2,4-oxadiazole (13.0 g) wasrefluxed in diethylamine (102 ml, 72.4 g) dissolved in methanol (520 ml)and ethanol (200 ml) for 1.5 hr. The solution was treated with charcoal,filtered, and evaporated. The residue was recrystallised from aqueousmethanol to give the amide (11.7 g, 82.5%), m.p. 118°, λ_(max). (EtOH)305.5 nm (ε 26,100), λ_(infl). 234.5 nm (ε 12,700) ν_(max). (CHBr₃) 1529and 1349 (NO₂), 1666 (--CON<), 838 (p-C₆ H₄), 974 cm.sup.⁻¹(trans-CH=CH).

3-trans-p-Aminostyryl-5-diethylcarbamoyl-1,2,4-oxadiazole

5-Diethylcarbamoyl-3-trans-p-nitrostyryl-1,2,4-oxadiazole (11.2 g) wasdissolved in acetone (250 ml) and acid titanous chloride solution (15%W/V; 260 ml) was added to the stirred solution during 1 hr. The pH wasadjusted to 7 and the solid that separated was filtered off anddissolved in acetone. The acetone solution was filtered and evaporated,leaving the crude amine (10.7 g,>100%), m.p. 174°-180°, ν_(max). (Nujol)3435-3130 (bonded NH₂), 1645 (--CON<), 812 (p-C₆ H₄, 962 cm.sup.⁻¹(trans-CH=CH), τ (Me₂ SO d6) 4.36 (NH₂).

EXAMPLE 68

    ______________________________________                                        Tablet                                                                        3-α-naphthyl-5-diethylcarbamoyl-1,2,4-oxadiazole                                                    500 mg                                            Lactose                     60 mg                                             Gum Acacia                  30 mg                                             Magnesium stearate          10 mg                                             ______________________________________                                    

The active ingredient was taken up in sufficient water to form agranulating fluid and the pH value adjusted to about 5.0 with the aid ofcitric acid. The gum acacia was dissolved in the same solution and thissolution was used to granulate the lactose. The granules were passedthrough a 20 mesh (B.S.) sieve, dried, lubricated with the magnesiumstearate and compressed.

EXAMPLE 69 Tablet

Tablets were prepared as described in Example 51 using half quantitiesof excipients and 250 mg. per tablet of3-p-methylthiostyryl-5-diethylcarbamoyl-1,2,4-oxadiazole as activeingredient.

EXAMPLE 70

    ______________________________________                                        Hard gelatin capsules                                                         3-α-naphthyl-5-diethylcarbamoyl-                                        1,2,4-oxadiazole        250 mg                                                Lactose                 47 mg                                                 Magnesium stearate      3 mg                                                  ______________________________________                                    

The active ingredient and the lactose were blended togetherhomogeneously. The magnesium stearate was also blended in to providegood flow properties and the powder distributed into hard gelatincapsules so that each contained 250 mg. of the active ingredient.

EXAMPLE 71

    ______________________________________                                        Eye Drops (Oily)                                                              3α-naphthyl-5-diethylcarbamoyl-                                         1,2,4-oxadiazole             0.1 % w/v                                        Castor oil            to     100 %                                            ______________________________________                                    

The active ingredient was reduced to a fine state by sub-division to aparticle size of less than 10μ. The castor oil was sterilised by heatingin a hot air oven at 160° C. The active ingredient was sterilised anddispersed in the sterile castor oil to yield a homogeneous mixture.

EXAMPLE 72

    ______________________________________                                        Eye Drops (aqueous)                                                           5-diethyl carbamoyl-3-biphenylyl-                                             1,2,4-oxadiazole           0.1 %                                              Sodium chloride            0.9 %                                              Phenyl ethanol             0.4 %                                              Benzalknoium chloride      0.002 %                                            Water (for injection)                                                                              to    100 %                                              Methyl cellulose           a sufficient amount                                                           to yield a final                                                              product with a                                                                viscosity of not                                                              less than 3000                                                                centistokes.                                       ______________________________________                                    

The methyl cellulose, sodium chloride, phenyl ethanol and benzalkoniumchloride were dissolved in the water and sterilised by heating in asealed container in an autoclave. The sterile micro-fine (particle size<10μ) active ingredient was then suspended in the sterile vehicle.

EXAMPLE 73

    ______________________________________                                        Eye Ointment                                                                  3α-naphthyl-5-diethylcarbamoyl-                                         1,2,4-oxadiazole       0.1 %                                                  Neomycin sulphate      0.5 %                                                  Liquid paraffin        20.0 %                                                 Soft paraffin          to  100.0 %                                            ______________________________________                                    

The paraffins were mixed, melted and strained, and were then sterilisedby heating in a hot air oven at 160° C. The sterile micro-fine (particlesize <10μ) active ingredient and neomycin sulphate were then suspendedand homogeneously dispersed in the paraffin.

EXAMPLE 74

    ______________________________________                                        Nasal Spray                                                                   3α-naphthyl-5-diethylcarbamoyl-                                                                0.1 %                                                  1,2,4-oxadiazole                                                              Methyl cellulose       0.5 %                                                  Glycerin               30.0 %                                                 Sodium chloride        0.5 %                                                  Nipa 82121             0.05 %                                                 Distilled water        to  100.0 %                                            ______________________________________                                    

The Nipa 82121, which is a mixture of the methyl, ethyl, propyl andbutyl esters of para hydroxy benzoic acid, was dissolved in hot water,and the solution cooled to room temperature. The methyl cellulose,glycerin and sodium chloride were then dissolved in the Nipa 82121. Thesolution was clarified by filtration and the micro-fine activeingredient (particle size <10μ) suspended in it.

EXAMPLE 75

    ______________________________________                                        Tablets                                                                       5-Diethylcarbamoyl-3-trans-p-methylsulphinylstyryl-                           1,2,4,-oxadiazole          250 mg                                             Polyethylene Glycol 6000   7.5 mg                                             Magnesium Stearate         2.5 mg                                             ______________________________________                                    

The active ingredient is ground to a powder having a particle sizebetween 1 and 10 microns. It is then granulated with the aid of achloroform solution of the polyethylene glycol by passing it through aNo. 12 mesh British standard sieve, and dried in vacuo. The driedgranulate is passed through a No. 16 mesh British standard sieve. Thegranulate is then blended with the magnesium stearate which acts as alubricant and compressed on 8 mm punches, preferably having a breakline.Each tablet weighs 260 mg. These tablets may if desired be film-coatedin conventional manner.

We claim:
 1. A compound selected from the group consisting of3-adamantylcarbamoyl-1,2,4-oxadiazole,5-diethylcarbamoyl-3-α-naphthyl-1,2,4-oxadiazole,5-α-naphthyl-3-dimethylcarbamoyl-1,2,4-oxadiazole,5-piperidinocarbonyl-3-p-methoxyphenyl-1,2,4-oxadiazole,5-piperidinocarbonyl-3-α-naphthyl-1,2,4-oxadiazole,5-dimethylcarbamoyl-3-α-naphthyl-1,2,4-oxadiazole,5-di-n-propylcarbamoyl-3-α-naphthyl-1,2,4-oxadiazole and3-biphenylyl-5-diethylcarbamoyl-1,2,4-oxadiazole.
 2. A compound asclaimed in claim 1, said compound being3-adamantylcarbamoyl-1,2,4-oxadiazole.
 3. A compound as claimed in claim1, said compound being 5-diethylcarbamoyl-3-α-naphthyl-1,2,4-oxadiazole.4. A compound as claimed in claim 1, said compound being5-α-naphthyl-3-dimethylcarbamoyl-1,2,4-oxadiazole.
 5. A compound asclaimed in claim 1, said compound being5-piperidinocarbonyl-3-p-methoxyphenyl-1,2,4-oxadiazole.
 6. A compoundas claimed in claim 1, said compound being5-piperidinocarbonyl-3-α-naphthyl-1,2,4-oxadiazole.
 7. A compound asclaimed in claim 1, said compound being5-dimethylcarbamoyl-3-α-naphthyl-1,2,4-oxadiazole.
 8. A compound asclaimed in claim 1, said compound being5-di-n-propylcarbamoyl-3-α-naphthyl-1,2,4-oxadiazole.
 9. A compound asclaimed in claim 1, said compound being3-biphenylyl-5-diethylcarbamoyl-1,2,4-oxadiazole.